Stereoselective synthesis of putative diol epoxide metabolites of 4H

Stable Ion Studies of the Chrysene Skeleton. Protonation of Chrysene, 6-Halochrysenes, 6-Acetylchrysene, and 4H-Cyclopenta[def]chrysene: NMR Studies o...
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J. Org. Chem. 1995,60, 4905-4911

4905

Stereoselective Synthesis of Putative Diol Epoxide Metabolites of 4H-C yclopenta[defl chrysene Wei Dai, Elias Abu-Shqara, and Ronald G. Harvey* Ben May Institute, University of Chicago, Chicago, Illinois 60637 Received February 24, 1995@

Syntheses of the anti-diol epoxide derivatives of the methylene-bridged polycyclic aromatic hydrocarbon 4H-cyclopenta[deflchrysenein both the bridge- and non-bridge-substituted rings (2 and 3) and the syn-diol epoxide derivative in the non-bridge-substituted ring (14) are described. These compounds are suspected to be active carcinogenic metabolites of the parent hydrocarbon. They are the first examples of the diol epoxide derivatives of a nonalternant methylene-bridged tumorigenic hydrocarbon to be synthesized. The bridge-substituted anti-diol epoxide derivative 2 is relatively stable, despite its relatively strained structure, and it possesses a unique “locked” structure which severely restricts conformational interconversion.

Introduction Methylene-bridged polycyclic aromatic hydrocarbons

(PAHs)are a relatively underinvestigated class of nonalternant polyarenes2 that are produced in the combustion of organic matter at moderate temperature^.^ They are present in relatively high abundance in crude petroleum2 and are widespread environmental pollutants. Some members of this class, e.g. 4H-cyclopenta[deflchrysene (1)exhibit mutagenic and tumorigenic properties.4 In order to make methylene-bridged PAHs more readily available for chemical and biological investigations, we recently undertook to develop more eficient synthetic approaches5 and to investigate patterns of electrophilic substitution of PAH molecules of this clam6 While the mechanism of metabolic activation of carcinogenic alternant PAHs, such as benzo[alpyrene, has been intensively investigated and diol epoxide metabolites have been identified as the principal active species ~,~ PAHs that bind covalently to DNA in v i ~ o ,nonalternant have received relatively little attention8 and virtually nothing is known concerning the mode of metabolic activation of the methylene-bridged PAHs. The likely pathways of activation (Figure 1)include, in addition to formation of diol epoxide metabolites in either bridge (2) or non-bridge (3) rings, an alternative pathway involving oxidation on the bridge positions to form alcohol intermediates (4) which undergo enzymatic conversion to reactive sulfate esters (5) which can give rise to carAbstract published in Advance ACS Abstracts, July 1, 1995. (1)A preliminary account of some of this work has been published without experimental detail: Harvey, R. G.; Luna, E.; Lee, H.; Pataki, J.; Dai, W.; Abu-Shqara, E. Polycycl. Arom. Compds. 1994,5,43. (2)Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry and Carcinogenicity, Cambridge University Press, Cambridge, England, @

1991. (3)Blumer, M. Sci. A m . 1976,234,35.Adams, J . D.;LaVoie, E. J.; Hoffmann, D. J . Chromatogr. Sci. 1982,20,274. (4)Rice, J.;Jordan, K.; Little, P.; Hussein, N. Carcinogenesis 1988, 9, 2275. (5) (a) Yang, C.; Harvey, R. G. Tetrahedron 1992,48,3775. (b) Yang, C.; Harvey, R. G. J.Org. Chem. 1993,58,4155.(c) Yang, C.; Yang, D. T. C.; Harvey, R. G. Synlett 1992,799. (6)(G)Abu-Shqara,E.; Yang, C.; Harvey, R. G. J . Org. Chem. 1992, 57,3312. (7)Harvey, R. G.;Geacintov, N. E. Acc. Chem. Res. 1988,21,66. ( 8 ) Metabolic activation of fluoranthene and several benzofluoranthenes have been studied: Day, B. W.; Sahali, Y.; Hutchins, D. A.; Wildschutte, M.; Pastorelli, R.; Nguyen, T. T.; Naylor, S.; Skipper, P. L.; Wishnok, J . S.; Tannenbaum, S. R. Chem. Res. Toxicol. 1992,5, 779.Weyand, E. H.; Bryla, P.; Wu, Y.; He, Z.-M.; LaVoie, E. J. Ibid. 1993,6,117.Weyand, E. H.; Cai, Z.-W.; Wu, Y.; Rice, J. E.; He, Z.-M.; LaVoie, E. J. Ibid. 1993,6,568.

‘1‘

1

&& _c

\

\

/

4

OH

/

5

OS03H

Figure 1. Potential pathways of metabolic activation of 4Hcyclopenta[deflchrysene(1). The diol epoxides 2 and 3 are the anti-isomers.

bonium ion intermediates capable of bonding covalently to nucleic The feasibility of the diol epoxide mechanism is supported by the identification of a diol epoxide metabolite in the bridge-substituted ring as an active form of 1,ll-methanocyclopenta[alphenanthren17-one (6h9 Evidence for activation by oxidation on bridge sites is provided by recent findings that synthetic bridge alcohol derivatives of methylene-bridged PAHs, notably 4, are activated to mutagens by sulfotransferase enzymes in the presence of 3’-phosphoadenosine-5’phosphosulfate.1° More detailed investigations of these potential mechanisms requires synthetic access to the key active metabolites. We reported recently an efficient method for the synthesis of the bridge alcohol and ketone derivatives of methylene-bridged PAHs, including 4.11We now wish to report syntheses of the anti-diol epoxide (9)Clayton, A. F. D.; Coombs, M. M.; Henrick, K.; McPartlin, M.; Trotter, J . Carcinogenesis 1983,4,1569.Hadfield, S.T.; Bhatt, T. S.; Coombs, M. M. Carcinogenesis 1984,5, 1485. (lO)Glatt, H.; Henschler, R.; Frank, H.; Seidel, A.; Yang, C.; Abu-shqara, E.; Harvey, R. G.Carcinogenesis 1993,14,599. Glatt, H.; Seidel, A,; Harvey, R. G.; Coughtrie, M. W. H. Mutagenesis 1994,9, 553.Glatt, H.; Pauly, K.; Frank, H.; Seidel, A.; Oesch, F.; Harvey, R. G.; Werle-Schneider, G. Carcinogenesis 1994,15, 2605. (11)Harvey, R. G.; Abu-shqara, E., Yang, C. J. Org. Chem. 1992, 57,6313.

0022-326319511960-4905$09.00/00 1995 American Chemical Society

4906

J. Org. Chem., Vol. 60, No. 15, 1995

Diol Epoxide Metabolites of 4H-Cyclopenta[deflchrysene Scheme 1

--

-

Me0

Ea: R = R' L OMe, R" R"'- H b: R R' = OMe, R" = H; R"' = Et c: R R'- H, R'- OMe; R"'= Me d: R = R' = H , R" OMe; R"'= Me

-

1 derivatives of the methylene-bridged polycyclic aromatic hydrocarbon 4H-cyclopenta[deflchrysene in both the bridge- and non-bridge-substituted rings (designated herein as the A ring and D ring, respectively) and the syn-diol epoxide derivative of this hydrocarbon in the nonbridge-substituted ring.12

Results Development of a new synthetic strategy, rather than modification of methods devised earlier for the synthesis of the diol epoxide metabolites of alternant polyarenes, such as chrysene and 5-methylchrysene,13 was necessitated by the presence of the methylene bridge in the target molecules. The synthetic approach to the oxidized metabolites of 4H-cyclopenta[deflchrysene in the D-ring (Le. 3) is based on the key intermediate 6,7-dimethoxy4H-cyclopenta[deflchrysene (7a)which contains the complete carbon skeleton as well as protected oxygen atoms for subsequent conversion to the dihydrodiol function (Scheme 1). An attractive potential synthetic route to 7a is via photocyclization of an appropriately substituted benzylidene derivative of acenaphthene. However, synthesis of an unsubstituted analog of 7a via an analogous route is reported to afford poor yields in both the preparation of the precursor and its photo~yc1ization.l~ The low yield in the latter step was suggested to be due to the distance between the reactive centers and the strain in the reaction intermediate. For this reason, it was considered desirable to employ a less strained intermediate (8a)in the photocyclization step and introduce the five-membered ring by subsequent acid-catalyzed cyclization of a carboxylic ester substituent. This has precedent in the report that photoreactions of the monomethoxy derivatives 8c and 8d afford good yields (37-70%) of cyclized products.15 Condensation of 1-naphthylacetic acid with 2,3-dimethoxybenzaldehyde in the presence of acetic anhydride and triethylamine furnished smoothly the carboxylic acid 8a. In order to avoid lactone formation under photolysis (12)In Figure 1 are shown the anti-diol epoxide isomers in both the bridge (2) or non-bridge (3)rings of 4H-cyclopenta[deflchrysene. These isomers are defined as the diastereomers which contain the epoxide oxygen atom and the benzylic hydroxyl group on opposite faces of the molecule. The syn-isomers, not shown, have these groups on same face of the molecule. (13)Harvey, R. G.;Pataki, J.; Lee, H. J. Org. Chem. 1986,51,1407. Pataki, J.; Lee, H.; Harvey, R. G. Carcinogenesis. 1983,4 , 399. (14)Nagel, D.L.; Kupper, R.; Antonson, K.; Wallcave, L. J. Org. Chem. 1977,42,3626. (15)Amin, S.; Camanzo, J.; Huie, K.; Hecht, S. S. J. Org. Chem. 1984,49,381.

9s: R = H b: R = Et

b:R-H C: R = AC

conditions,16the acid 8a was converted to the ethyl ester derivative 8b. Oxidative photocyclization of 8b with IZ and propylene oxide provided the chrysene ester derivative 9b in 90% yield. Similar reaction in the absence of propylene oxide furnished 9b in lower yield (~50%).~~ The second cyclization step was carried out in liquid HF at room temperature. Although decarboxylation is a relatively facile process for carboxylic acids in sterically crowded bay regions, no loss of the carboxylic ester function was detected under these mild conditions. However reaction was slow, with only -40% completion after 3 days.ls The low rate was rationalized as due to the poor solubility of the ester and/or the free acid in the HF medium. With the use of CHzClz as cosolvent and a decreased volume of HF, reaction time could be cut from 3 days to 1 day. Under these conditions, the ketone product 10 was obtained in 94% yield. Attempts to directly reduce the carbonyl group of 10 by the HuangMinlon modification of the Wolff-Kishner method were unsuccessful, affording only trace amounts of the desired reduction product 7a along with more polar impurities. More satisfactory results were obtained by a two-step sequence in which condensation of the ketone 10 with anhydrous hydrazine in refluxing diethylene glycol for 3 h was carried out to generate a hydrazone intermediate which was decomposed by refluxing with 2% aqueous NaOH. The overall yield of 7a was 85%. Conversion of 7a to the trans-6,7-dihydroxy-6,7-dihydro-4H-cyclopenta[deflchrysene(1la) was readily accomplished by deprotection of the methyl groups by treatment with BBr3 followed by reduction of the hydroquinone product 7b with NaBH4 (Scheme 2). Purification of 7b by recrystallization was unsatisfactory. Like other PAH catechols, 7b was air-sensitive, changing color from white to reddish after a few days at room temperature, indicative of oxidation to the corresponding oquinone. However, its structure was readily confirmed by diacetylation with acetic anhydride and pyridine to the stable diacetate 7c which could be readily purified. Reduction of 7b with N a B a in EtOH was conducted with 02 bubbling through the solution. It is likely that the mechanism of this process is more complex than a simple direct reduction (see D i s c u s ~ i o n ) . ~Reductions ~-~~ of this (16) Lee-Ruff, E.; Kruk, H.; Katz, M. J. Org. Chem. 1984,49,553. (17) Propylene oxide is reported to enhance yields in photocyclization by scavenging the HI produced: Liu, L.; Yang, B.; Katz, T. J.; Poindexter, M. K. J. Org. Chem. 1991,56,3769. (18)Extent of reaction after 3 days was determined by 'H NMR analysis of an aliquot.

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Dai et al.

J. Org. Chem., Vol. 60, No. 15, 1995 4907

Scheme 2 7a

1'BBr3

- # -

2. NaBHA,0, -

R

RO

Scheme 3 m-CPBA

-

3

@ V 1la:R-H b: R AC

14a: R

NBS/

Br,,.,.,

--

b: R

R

H Me

A, PdIC

,@-

15a:R=O,R'=H b: R P H ~R'D , H C:R-H?,R'=CH~

r-BuOK

HO""

HO""'

Ho

12

0

Ho

13

17 16a: R = CH, type are known to be highly trans-stereosele~tive.~~ The b:R-H lla and its diacetate (llb) were 'H NMR spectra of 1. NaBH, 2. A. Pd/C entirely consistent with assignment of lla as trans-6,7dihydroxy-6,7-dihydro-4H-cyclopenta[deflchrysene. The value of the coupling constant J 6 , 7 = 11.3 Hz for lla indicates that like other nonsterically hindered dihydrodiols it exists predominantly as the diequatorial 18a: R = Me b:R=H conformer.lg Conversion of 1la to the corresponding anti- and synthe unsubstituted analog of 15b underwent preferential diol epoxide derivatives was carried out by standard cyclization to the 5-position adjacent to the five-memmethods (Scheme 2).21323Epoxidation of lla with mbered ring to furnish the undesired i ~ o m e r ,while ~~,~~ chloroperbenzoic acid provided the corresponding anticyclization of the fully aromatic compound took place diol epoxide, trans-6,7-dihydroxy-anti-8,9-epoxy-6,7,8,9regioselectively to the 7-position. Esterification of 15b tetrahydro-4H-cyclopenta[&flchrysene (31,in good overall furnished the methyl ester 15c which underwent dehyyield. Reaction of lla with N-bromosuccinimide in moist drogenation over a 10% Pd/C catalyst to provide the fully acetonitrile-THF gave the corresponding bromohydrin aromatic ester 16a. Hydrolysis of 16a followed by 12. Treatment of 12 with t-BuOK furnished smoothly cyclodehydration of the free acid 16b in liquid HF gave the corresponding syn-diol epoxide, trans-6,7-dihydroxysyn-8,9-epoxy-6,7,8,9-tetrahydro-4H-cyclopenta~de~chry- a single isomeric ketone product whose 500 MHz lH NMR spectrum permitted assignment as the desired ketone sene (13). The lH NMR spectra of 3 and 13 were in good structure 17 arising from cyclization to the 7-position. agreement with their assignments. The coupling conThis isomer was readily distinguished from the ketone stants observed for the H6,7 protons are consistent with formed by cyclization to the alternative ring position by the existence of both diol epoxide isomers predominantly the presence of a characteristic low field doublet at 6 9.18 in a conformation in which the hydroxy groups are for Hlo due to the anisotropic effect of the carbonyl group oriented diequatorially, in agreement with previous in the sterically hindered bay region and a singlet a t 6 findings for other similar compounds.23 7.49 for the H5 aromatic proton adjacent to the fiveSynthesis of the anti-diol epoxide isomer in the A-ring membered ring, in addition to other expected peaks. of 4H-cyclopenta[deflchrysene(2)was accomplished via Reduction of the keto group of 17 with NaBH4 furnished a synthetic route based on the key intermediate 2-hythe corresponding alcohol which on heating with 10% droxy-4H-cyclopenta[deflchrysene (18b). This phenol was itself prepared from 2-methoxy-8,9-dihydro-4H-cy- Pd/C underwent concurrent dehydration and dehydrogenation to yield 2-methoxy-4H-cyclopenta[deflchrysene clopenta[deflphenanthrene (14b)which contains one less (Ma). Demethylation of 1Sa with BBr3 provided 2-hyaromatic ring (Scheme 3). Synthesis of 14a was previdroxy-4H-cyclopenta[chrysene (1Sb). Good yields ously d e s ~ r i b e d . ~Friedel-Crafts "~~~ reaction of 14b with were obtained in all steps for an overall yield of 18b from succinic anhydride and took place regiospecifically 14b of 31%. in the 6-position to furnish the keto-acid 15a. This site Conversion of 18b to the corresponding dihydrodiol was of substitution is in accord with expectation based on accomplished by oxidation with an aqueous solution of prior findings that the 8,g-dihydro derivatives of 4HFremy's salt in a two phase system with CHzClz and the cyclopenta[deflphenanthrene behave as biphenyl derivaphase transfer agent Adogen 464 to furnish the related tives in electrophilic s u b s t i t u t i ~ n s . ~Wolff-Kishner "~~~~~ o-quinone derivative (19)(Scheme 4). Reduction of 19 reduction of the keto group of 15a with hydrazine and with NaBH4 in MeOH in the presence of 0 2 yielded trunsKOH took place smoothly to provide the reduced acid (20). 1,8dihydroxy-1,2-dihydro-4H-cyclopnta[deflchrysene 15b. It was necessary to dehydrogenate 15b prior to While the NMR data were consistent with this assignacid-catalyzed cyclodehydration, since it was previously ment, an unusual feature of the spectrum was the observed that relatively low value of the coupling constant for the (19) Reference 2, Chapter 13, pp 306-329. hydrogen atoms in the hydroxylated positions ( J 1 , Z = 6.0 (20) Platt, K. L.; Oesch, F. Synthesis 1982,459. Hz); the usual range of values for other structurally (21) Harvey, R. G. in Polycyclic Hydrocarbons and Carcinogenesis; Harvey, R. G., Ed., American Chemical Society Symposium Series, similar nonsterically hindered terminal ring dihydrodiols American Chemical Society: Washington, D. C., 1985; pp 35-62. is 7.6-11 H Z . This ~ ~may ~ indicate that the conforma(22) Platt, K. L.; Oesch, F. J. Org. Chem. 1983,48,265.

\

(23) Reference 2, Chapter 14,pp 330-359. Harvey, R. G. Synthesis 1986,605. (24) Minabe, M.; Yoshida, M.; Amimoto, T.; Nagata, T.; Kobori, M. Bull. Chem. SOC.Jpn. 1988,61, 879.

~~

(25) Harvey, R. G. in The Conformational Analysis of Cyclohexenes, Cyclohexadienes, and Related Hydroaromatic Compounds; Rabideau, P. W. Ed.; VCH Publishers: New York, 1989; pp 267-298.

4908 J. Org. Chem., Vol. 60, No. 15, 1995

Diol Epoxide Metabolites of 4H-Cyclopenta[deflchrysene

Scheme 4

sion of 6,7-dimethoxy-4H-cyclopenta~deflchrysene (7a)to the desired dihydrodiol l l a was effected efficiently by demethylation with BBr3 to the hydroquinone 7b followed directly by reduction of the air-sensitive 7b with NaBH4 with O2 bubbling through the solution. Although the reduction of PAH hydroquinones to dihydrodiols was first 19 reported more than a decade ago,2oit has seen minimal application in synthesis.22,2sThe mechanism is believed OH to involve initial oxidation of 7b to a quinone intermediate by molecular 0 2 followed by trans-stereospecific reduction of the quinone to the dihydrodiol l l a . The overall synthetic route to l l a provides an efficient method for its synthesis from available compounds. The 20 method is conveniently adaptable to the synthesis of l l a and the corresponding anti- and syn-diol epoxides on tional equilibrium is shifted in favor of a higher ratio of preparative scale. The photocyclization step, which is the diaxial conformer or that the substituted ring is often limiting in multistep syntheses because of the need distorted from the normal configuration by the rigidity to conduct reactions in extremely dilute solutions, is not imposed by the methylene bridge. Epoxidation of 20 with a serious limitation in the present case, and good yields m-chloroperbenzoic acid gave the corresponding anti-diol epoxide, trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tet- are obtained even with concentrated solutions. The A-ring diol epoxide isomer of 4H-cyclopenta[deflrahydro-4H-cyclopenta[deflchrysene(2), in good overall chrysene (2) is the first example of a diol epoxide in which yield. Despite its apparently strained ring structure, this a methylene-bridge is covalently linked to the saturated diol epoxide derivative appeared to be relatively stable, ring bearing an epoxide function. Although an analogous showing no evidence of spontaneous decomposition on diol epoxide metabolite was postulated to be the active storage as found for some other similar compounds, e.g. form of l,ll-methanocyclopenta[alphenanthren-17-one the anti-diol epoxide of 7,12-dimethylbenz[aIanthracene (61,s its synthesis was not reported. The relative stability which decomposes within a few hours of its preparaof 2, despite its relatively strained structure, is somewhat tion.26,27 surprising. On the other hand, diol epoxide isomers of fluoranthene and benzo[jlfluoranthene, which are also Discussion highly strained due to the presence of the epoxide ring Convenient syntheses are described for the diol epoxide a t a ring juncture, are also table.^^,^^ Although the derivatives in both terminal rings of 4H-cyclopenta[deflfavored conformation of carcinogenic PAH diol epoxide chrysene (1). While syntheses of the diol epoxide memetabolites in solution is d i e q ~ a t o r i a l ,the ~ ~ ,energy ~~ tabolites of several alternant PAHs have been previously barrier for conformational interconversion is low and it reported,23these are the first examples of diol epoxides is uncertain whether this orientation is retained in of a methylene-bridged PAH. subsequent reactions with nucleic acids. Since the structure of 2 is relatively rigid, investigation of its The presence of the methylene group in 4H-cyclopentareactions with DNA may aid understanding of the role [deflchrysene necessitated new synthetic strategies. Synthesis of the oxidized metabolites in the D-ring was of conformation in the interaction of diol epoxides with accomplished via a route involving oxidative photocynucleic acids. clization of an o-dimethoxy-substituted derivative 8b.The Biological Studies. Recently completed tumorigepresence of a single unsubstituted ortho position in this nicity experiments confirm that both anti-diol epoxide precursor predetermined that cyclization would occur (2 and 3) derivatives of 4H-cyclopenta[deflphenanthrene regiospecifically to form a single isomer. This precursor are potent tumorigens in newborn mice.31 The A-ring diol had the additional advantage that the dimethoxyepoxide 2 was the most active compound of the chrysene substituted product could be converted in a later stage derivatives tested, showing greater activity than 3 which of the synthesis to the desired dihydrodiol intermediate was more active than the anti-diol epoxide derivative of in two steps, i.e. deprotection and reduction with NaBH4, chrysene itself. whereas the established synthetic route to molecules of this type via a monomethoxy-substituted intermediate13 Experimental Section requires three steps, deprotection, oxidation to a quinone Materials and Methods. 2-Hydroxy-8,9-dihydro-4H-cywith Fremy's salt, and reduction with NaBH4. Prior to clopenta[deflphenanthrene(14a)was synthesized from 8,9the introduction of the dihydrodiol function, it was dihydro-4H-cyclopenta[deflphenanthrenevia acetylation5"folnecessary to carry out a second cyclization step to introduce the five-membered cyclopentano ring. This was (28) Syntheses of dihydrodiol derivatives of chrysene and dibenzoaccomplished by cyclodehydration of the carboxylic ester [defiplchrysene (dibenzo[a,llpyrene) via reduction of protected hydro9b in liquid HF. It is notable that reaction time could quinones are described by Seidel, A,; Bochnitschek, W.; Glatt, H.; Hodgson, R. M.; Grover, P. L.; Oesch, F. in Polynuclear Aromatic be decreased and the yield markedly enhanced by the Hydrocarbons : Measurements, Means and Metabolism; Cooke, M., use of CHzClz as cosolvent. This modification may be Loening, K., Meritt, J., Eds.; Battelle Press: Columbus, OH, 1991; pp useful in cyclodehydrations of other large PAH com801-817. Luch, A.; Glatt, H.; Platt, K. L.; Oesch, F.; Seidel, A. Carcinogenesis 1994,15,2507. pounds which are poorly soluble in liquid HF. Conver0

(26) Lee, H.; Harvey, R. G. J . Org. Chem. 1986,51,3502. (27) Most diol epoxides are relatively reactive, hydrolizing readily in aqueous media and decomposing on exposure to mild acids or on heating.Ig Despite their sensitivity, they are sufficiently stable to conduct a wide range of biological studies.2

(29) Rastetter, W. H.; Nachbar, R. B., Jr.; Russo-Rodriguez, S.; Wattley, R. V.; Thilly, W. G.; Andon, B. M.; Jorgensen, W. L.; Ibrahim, M. J . Org. Chem. 1982,47,4873. (30) He, Z.-M.; Rice, J. E.; LaVoie, E. J . J . Org. Chem. 1992,57, 1784. (31)Amin, S.;Desai, D.; Dai, W.; Harvey, R. G.; Hecht, S. S. Carcinogenesis, submitted.

Dai et al. lowed by Baeyer-Villeger oxidation and alkaline hydrolysis of the product by the method of Minabe et aLZ48,g-Dihydro4H-cyclopenta[deflphenanthrene was prepared from 4H-cyclopenta[deflphenanthrene by the published procedure^.^^^^^^^^ Fremy's salt [(S03K)zNO] was prepared according t o the literature method34and used fresh. m-Chloroperbenzoic acid (Aldrich) was purified by washing with pH 7.4 phosphate buffer and drying under reduced pressure. N-Bromosuccinimide was crystallized from water prior to use. Methyltrialkyl(Cs-Cl-Jammonium chloride (Adogen 464) was purchased from Aldrich. THF was distilled from sodium benzophenone ketyl. All of melting points are uncorrected. The W spectra were measured on a Perkin-Elmer Lamda 5 spectrometer. lH NMR spectra were obtained on the University of Chicago 300- or 500-MHz lH NMR spectrometers in CDC13 with tetramethysilane as internal standard unless stated otherwise. 3-(2,3-Dimethoxyphenyl)-2-(1-naphthyl)propenoic Acid (Sa). A solution of 1-naphthylacetic acid (16.8 g, 90 mmol) and 2,3-dimethoxybenzaldehyde(15.0 g, 90 mmol) in AczO (100 mL) and Et3N (50 mL) was stirred a t 120 "C until TLC showed complete conversion of the starting acid (12 h). The solution was cooled t o 0 "C, quenched with concentrated HC1, and extracted with CHC13. The organic layer was dried over MgS04. After removal of the solvent under vacuum, recrystallization from hexane-ethyl acetate-acetic acid gave Sa (21.9g, 72%) as colorless crystals shown by NMR to be a mixture of cis- and trans-isomers: lH NMR 6 8.56 (s, 11,7.897.30 (m, 71, 6.72 (d, 1,J = 9.1 Hz), 6.47 (t, 1,J = 8 Hz), 6.05 (d, 1,J = 8 Hz), 3.94 and 3.81 (2s, 6). MS, mle 334 (M+, 941, 303 (271, 288 (291, 257 (18). Anal. Calcd for C21H1804: C, 75.43; H, 5.43. Found: C, 75.14; H, 5.31. Ethyl 3-(2,3-Dimethoxyphenyl)-2-(1-naphthyl)propenoate (Sb). The acid Sa (21.9 g, 66 mmol) was converted to the ethyl ester by heating at reflux in EtOH (200 mL) with 2 mL of HzS04 for 24 h. The ester was obtained as pale yellow crystals (23.5 g, 99%) as a mixture of cis- and trans-isomers: l H N M R 6 8 . 4 2 ( ~1, ) , 7 . 7 7 - 7 . 2 3 ( m , 7 ) , 6 . 7 l ( d , l , J = 8 . 0 H z ) , 6.50 (t, 1, J = 8.0 Hz), 6.02 (d, 1,J = 8.0 Hz), 3.92 and 3.80 (2s, 6). MS, mle 362 (M+, 1001, 331 (161, 316 (181, 303 (21). Anal. Calcd for C23H2204: C, 76.22; H, 6.12. Found: C, 76.17; H, 6.16. 7,S-Dimethoxy-5-carbethoxychrysene (9b). Argon was bubbled through a solution of the ester Sb (2.5g, 6.9 mmol) and 12 (1.74 g, 6.9 mmol) in benzene (450 mL) for 30 min. Then propylene oxide (10 mL) was added, and the solution was irradiated with a Hanovia 450 W medium-pressure mercury lamp through a Pyrex filter. The course of reaction was monitored by TLC, and irradiation was stopped when the TLC showed the reaction to be complete (15 h). The solvent was concentrated t o 100 mL, washed with NazS~03(aq, 10%)and HzO, and dried over MgS04 The crude product was triturated with ether to give the ester 9b (2.23 g, 90%) as light yellow crystals, mp 183-184 "C: lH NMR 6 8.60 (d, 1,J = 9.1 Hz), 8.52 (s, 11, 8.47 (d, 1,J = 9.3 Hz), 8.22 (m, 11,8.00 (d, 11, 7.98 (m, 1) 7.59-7.55 (m, 2), 7.48 (d, l), 4.51 (9, 2, J = 7.2 Hz), 4.08 and 4.06 (2s, 6), 1.35 (t, 3, J = 7.2 Hz). MS, m le 360 (M+, 1001, 345 (141, 331 (71, 317 (8). Anal. Calcd for C23H2004: C, 76.65; H, 5.59. Found: C, 76.44; H, 5.56. 6,7-Dimethoxy-4H-cyclopenta[deflchrysen-4-one (10). To a solution of the ester 9b (2.3 g, 6.38 mmol) in CHzClz (100 mL) was added HF (20 mL) in a gas-tight Teflon jar. The color of solution changed instantly from orange to purple. The solution was stirred for 24 h, and then the solvent was removed by evaporation in a well ventilated hood. The solid product was triturated with saturated aqueous NaHC03 and washed with HzO and ether-hexane (1:9) to give the ketone 11 (1.9 g, 94%) as yellow crystals, mp 200-201 "C: lH NMR 6 8.64 (s, 11, 8.33 (d, 1,J = 9.0 Hz), 8.27 (d, 1,J = 8.9 Hz), 8.01(d, 1,J = 8.1 Hz), 7.96 (d, 11, 7.90 (d, 1,J = 7.0 Hz), 7.63 (dd, 11, 7.42 (d, 11, 4.07 and 4.06 (2s, 6). MS, mle 314 (M+,100),299 (281, 284 (291,271 (23). Anal. Calcd for C21H1403: C, 80.24; H, 4.49. Found: C, 80.11; H, 4.55. (32) Yang, C.; Harvey, R. G. Polycycl. Arom. Compds. 1992,2,229. (33) Fu,P. P.; Lee, H.; Harvey, R. G. J. Org. Chem. 1980,45,2797. (34)Wehrli, P. A.; Pigott, F. Org. Synth. 1972,52,83.

J. Org. Chem., Vol. 60, No. 15, 1995 4909 6,7-Dimethoxy-4H-cyclopenta[deflchrysene (7a). Ketone 10 (0.5 g, 1.6 mmol) was dissolved in diethylene glycol (50 mL) a t -120 "C, and then the solution was cooled below 100 "C. Anhydrous NHzNH2 (149 pL, 4.8 mmol) was slowly added and the reaction mixture was heated a t -130 "C until TLC showed disappearance of 10 (5 h). The solution was cooled again below 100 "C, and aqueous NaOH (2%, 10 mL) was added. The reaction mixture was refluxed for another 7 h, cooled, and poured into an ice cold NH40H aqueous solution (1.0 L). Filtration of this aqueous suspension gave crude 7a (0.41g, 85%) as a yellow solid, mp 179-180 "C: 'H NMR 6 8.44(d,l,J=8.7Hz),8.40(d,l,J=9.0Hz),8.32(s,1),7.97 (d, l),7.84 (dd, 1,J = 7.0 Hz, J = 2.0 Hz), 7.64 (d, 1,J = 7.0 Hz), 7.62 (t, l),7.42 (d, l),4.45 (s, 2), 4.06 and 4.05 (2s, 6). MS, mle 300 (M+, loo), 285 (41), 257 (351,242 (36). Anal. Calcd for C21H1602: C, 83.98; H, 5.37. Found: C, 83.98; H, 5.40. 6,7-Dihydroxy-4H-cyclopenta[deflchrysene (7b).To a solution of crude 7a (0.5g, 1.6mmol) in CH2C12 (100 mL) was added BBr3 (2 mL, 12 mmol) a t 0 "C. The resulting pale yellow suspension was warmed and stirred a t room temperature until TLC showed reaction to be complete (1h). Then the suspension was poured into ice cold aqueous NHdOH (600 mL). After stirring for 1h, the aqueous suspension was filtered to provide the crude catechol 7b (0.41g, 90%) as a colorless solid ('98% pure): lH NMR 6 8.46 (d,'l,J = 8.7 Hz), 8.33 (s, 11,8.20 (d, 1, J=9.0Hz),8.02(d,l,J=8.7Hz),7.86(d,J=8.1Hz),7.66 (m, 2), 7.30 (d, l),5.25 and 5.82 (2s, 21, 4.50 (s, 2). MS, mle 272 (M+, loo), 255 (9), 243 (121, 226 (26). HRMS, calcd for C19H1202: m /e 272.0837, found mle 272.0837. The instability of the catechol made further purification impractical. However, its identity was readily confirmed by conversion to its stable diacetate 7c by acetylation with Ac2O and pyridine by the method used to prepare the dihydrodiol diacetate llb. Data on 7c: mp 209-210 "C; lH NMR 6 8.58 (d, 1, J = 8.9 Hz), 8.45 (d, 1, J = 8.8 Hz), 8.01 (d, l), 7.99 (dd, 1, J = 4.1 Hz), 7.87 (dd, 1,J = 5.2 Hz), 7.68 (s, 11,7.67 (d, 11,7.50 (d, 11, 4.46 (s, 2), 2.51 and 2.36 (2s, 6). MS, mle 356 (M+, 411, 314 (42), 272 (loo), 243 (24). Anal. Calcd for C23H1604: C, 77.52; H, 4.53. Found: C, 77.40; H, 4.54. truns-6,7-Dihydroxy-6,7-dihydro-4H-cyclopenta[deflchrysene (lla). To a solution of 7b (0.7 g, 2.57 mmol) in 600 mL of absolute EtOH was added NaBH4 (2.5 g, 66 mmol) a t room temperature. The reaction mixture was stirred in the dark for 72 h with 0 2 slowly bubbling through the solution. The solvent was concentrated under vacuum without heating t o -50 mL and then poured into cold NH40H (saturated) and extracted with EtOAc. The organic layer was washed with HzO and dried over Na2S04. Trituration of the crude solid with ether gave the dihydrodiol 12a (0.65 g, 92%) as a white solid, mp 221- 222 "C: 'H NMR (CDC13-DMSO-ds-D20, 5:l: 1)6 8.02 (s, l), 7.89 (d, 1,J = 8.9 Hz), 7.77 (d, l,),7.74 (d, 1, J = 7.8 Hz), 7.63 (d, 1,J = 7.0 Hz), 7.56 (dd, 11, 7.12 (dd, 1,J =1.7Hz,J=9.8Hz),6.15(dd,1,J=9.8Hz),5.02(d,l,J= 11.3 Hz), 4.59 (dd, 1,J = 1.3 Hz), 4.29 (bs, 2); W (ethanol) A,,,= 269 (E 36 4501, 247 (34 3001, 221 (55 0701, 200 (21 500) nm. MS, mle 274 (M+, l),257 (191, 256 (1001, 239 (10). Anal. Calcd for C19H1402: C, 83.19; H, 5.14. Found: C, 83.06; H, 5.20. truns-6,7-Diacetoxy-6,7-dihydro-4H-cyclopenta[deflchrysene (llb). A solution of lla (0.40 g, 1.49 mmol) in Ac2O (25 mL) and pyridine (1mL) was stirred at room temperature for 24 h. The reaction mixture was poured over crushed ice (300 mL), and the mixture was stirred until the ice melted. The solid product was collected by a filtration and purified by flash column chromatography on Florisil (benzene:ether, 1:1). The diacetate l l b (0.45 g, 86%) was obtained as colorless crystals, mp 186-187 "C: lH NMR 6 7.96 (d, 1,J = 9.0 Hz), 7.84 (d, l), 7.78 (d, J = 6.7 Hz), 7.67 (s, 11,7.66 (dJ, J = 6.9 Hz), 7.61 (dd, l), 7.44 (d, 1, J = 9.8 Hz), 6.34 (d, 1, J = 4.7 Hz), 6.21 (dd, l), 5.57 (dd, 1, J = 4.5 Hz), 4.31 (s, 21, 2.10 (s, 3), 2.03 (s, 3). MS, mle 298 (M+ - AcOH, 261, 256 (1001, 239 (131, 226 (22). Anal. Calcd for C23H1804: C, 77.08; H, 5.06. Found: C, 77.12; H, 5.19. trans-6,7-Dihydroxy-un~-S,9-epoxy-6,7,8,9-tetr~ydro4H-cyclopenta[deflchrysene(3). To a solution of dihydrodiol lla (50mg, 0.18 mmol) in 120 mL of THF at 0 "C under

4910

J. Org. Chem., Vol. 60,No.15, 1995

Diol Epoxide Metabolites of 4H-Cyclopenta[deflchrysene

mL of diethylene glycol was refluxed for 24 h and then cooled and acidified with HC1. The usual workup afforded the reduced acid 15b (4.3 g, 78%), mp 126-128 "C (hexanebenzene): 'H NMR 6 7.12 (s, 11, 6.91 (s, 2),6.69 (5, 11, 3.83 (5, 3), 3.80 (s, 2), 3.07 (9, 41, 2.69 (t,2, J = 7.4 Hz), 2.37 (t, 2, J = 7.4 Hz), 1.96 (quin, 2, J = 7.4 Hz). Anal. Calcd for CzOH2003: C, 77.92; H, 6.49. Found: C, 77.64; H, 6.58. Methyl 8,9-Dihydro-2-Methoxy-4H-cyclopenta[&flphenanthrene-6-butyrate(15c). A solution of the acid 15b (4.0 g, 13 mmol) and p-toluenesulfonic acid (200 mg) in 150 mL of MeOH was heated at reflux for 24 h. The usual workup followed by chromatography on silica gel furnished the methyl ester 15c (3.55 g, 85%), mp 56-57 "C (hexane): 'H NMR 6 7.12 (s, 11,6.91 (s, 21, 6.70 (s, 11, 3.83 (s, 31,331 (s, 21, 3.67 (s, 3), 3.08 (s, 4), 2.67 (t, 2, J = 7.3 Hz), 2.36 (t, 2, J = 7.3 Hz), 1.96 (quin, 2, J = 7.4 Hz). Anal. Calcd for C21H2203: C, 78.23; H, 6.88. Found: C, 78.30; H, 6.83. Methyl 2-Methoxy-4H-cyclopenta[deflphenanthrene6-butyrate(16a). A solution of 15c (3.0 g, 9.3 mmol) in 60 8a-Bromo-6/l,7~9/l-trihydroxy-6,7,8,9-tetrahydro-4HmL of triglyme was heated with 1g of a 10% P d C catalyst at cyclopenta[&flchrysene (12). To a solution of NBS (44 mg, reflux for 6 h. Conventional workup followed by chromatog0.24 mmol) at 0 "C in CH~CN-THF-HZO (11mL, 5:5:1) at 0 raphy on silica gel afforded 16a (2.1 g, 70%) as colorless flakes, "C was added the dihydrodiol lla (65 mg, 0.24 mmol). The mp 86-87 "C (hexane): 'H NMR 6 7.75 (d, 2, J = 2.4 Hz), color of the solution changed from light yellow to light brown. 7.58 (s, l),7.49 (s, l),7.33 (s, 11, 7.23 (s, 1),4.28(s, 21, 2.97 (s, The mixture was allowed to slowly warm up to room temper3), 3.67 (s, 3), 2.92 (t, 2, J = 7.4 Hz), 2.39 (t, 2, J = 7.4 Hz), ature while stirring for 10 min. Unreacted NBS was destroyed 2.08 (quin, 2, J = 7.4 Hz). Anal. Calcd for C21H2003: C, 78.73; by addition of ice cold aqueous NazSz03 (10%). The mixture H, 6.29. Found: C, 78.73; H, 6.28. was extracted with Et0Ac:EtzO ( l : l , 3 x 50 mL) and dried 2-Methoxy-4H-cyclopenta[defl phenanthrene-6-butyrover MgS04, and the solvent was removed on a rotovap ic acid (16b). A solution of 16a (2.0 g, 6.2 mmol), 2 g of KOH, equipped with a dry ice condenser without heating. The crude 5 mL of water, and 50 mL of ethanol were heated at reflux for product was triturated with ether to furnish the bromohydrin 1h and then cooled and acidified with HC1. The usual workup 12 (77 mg, 86%) as a colorless solid which is decomposed at gave 16b (1.7 g, 89%) as white crystals, mp 166-167 "C 120 "C: 'H NMR (DMSO-& : CDC13 : DzO, 1:8:1) 6 8.08 (d, (benzene): lH NMR 6 7.74 (d, 2, J = 2.8 Hz), 7.71 (s, l),7.58 1,J = 9.1 Hz), 7.96 (s, l),7.84 (d, l ) , 7.77 (d, 1,J = 7.8 Hz), (s, l),7.49 (s, l), 7.22 (s, l),4.27 (s, 21, 3.97 (s, 31, 2.93 (t,2, J 7.64 (d, 1, J = 6.9 Hz), 7.60 (dd, 11, 5.70 (d, 1, J = 2.6 Hz), = 7.4 Hz), 2.40 (t, 2, J = 7.4 Hz), 2.08 (quin, 2, J = 7.4 Hz). 4.96 (d, 1, J = 7.7 Hz), 4.78 (dd, 1, J = 2.6 Hz), 4.33 (dd, l), Anal. Calcd for C20H18O3: C, 78.41; H, 5.92. Found: C, 78.34; 4.32 (bs, 2). MS, d e 370 (M+,301,353 (751,337 (34), 335 (15). H, 5.90. Anal. Calcd for C19H1503Br: C, 61.47; N, 4.07. Found: C, 2-Methoxy-6,7,8,9-tetrahydro-4H-cyclopenta[deflchry61.47; H, 4.12. HRMS, calcd for C19H1503Br: mfe 370.0208, sen-9-one(17). A solution of the acid 16b (1.2 g, 3.9 mmol) found mfe 370.0204. trune-6,7-Dihydroxy-eyn.8,9-epoxy-6,7,8,9-tetrahydro- in 50 mL of liquid HF was stirred for 24 h. The usual workup followed by chromatography on silica gel with CHzClz as eluent 4H-cyclopenta[deflchrysene(13). To a solution of the furnished the pure ketone 17 (1.04 g, 92%) as white crystals, bromohydrin 12 (8 mg, 0.02 mmol) in THF (8 mL) was added mp 184-185 "C: 'H NMR 6 9.18 (d, 1, J = 9.1 Hz), 7.92 (d, 1, a 0.08 M solution of t-BuOK in t-BuOH (3 mL, 0.24 mmol, J = 9.1 Hz), 7.49 (s, l),7.32 e, 11, 7.24 (s, 11, 4.22 (s, 21, 3.98 prepared from an Aldrich 1M solution of t-BuOK in t-BuOH) (s, 3), 3.22 (t, 2, J = 6 Hz), 2.80 (t, 2, J = 6 Hz), 2.25 (quin, 2, over a 20 min period at room temperature under argon. The J = 6 Hz). Anal. Calcd for C20H1602: C, 83.31; H, 5.59. reaction mixture was stirred at room temperature for 1h. The Found: C, 83.23; H, 5.58. mixture was poured into ice cold aqueous NH4C1(2% solution, 2-Methoxy-4H-cyclopenta[deflchrysene (18a). A solu20 mL) and extracted with ice cold ether-EtOAc ( l : l , 200 mL). tion of 17 (900 mg, 3.12 mmol) in dry THF (5 mL) and ethanol The organic layer was washed with ice cold HzO and dried (25 mL) under argon was cooled to 0 "C. NaBH4 (1 g) was over NazS04. Removal of the solvent under vacuum on a added over 10 min, and the mixture was stirred for 1h then rotovap equipped with a dry ice condenser afforded the worked up conventionally. A solution of the alcohol product colorless diol epoxide 13 (5.3 mg, 85%) as a colorless solid (830 mg) in 25 mL triglyme was heated at reflux with a 10% which decomposed a t 177 "C: lH NMR (DMSO-&) 6 8.28 (d, P d C catalyst for 5 h. The usual workup followed by chroma1,J = 8.9 Hz), 7.97 (d, 1,J = 8.9 Hz), 7.88 (d, 1, J = 8.0 Hz), tography on a silica gel column eluted with ether-hexane (1: 7.76 (s, 11, 7.75 (d, 1,J = 6.9 Hz), 7.65 (dd, 11, 4.82 (d, 1,J = 5) gave 18a (530 mg, 62%) as a white solid, mp 188-190 "C: 3.7 Hz), 4.69 (d, 1,J = 3.0 Hz), 4.38 (bs, 21, 3.83 (m, 1). MS, lH NMR 6 8.63 (dd, 1, J = 7.9 Hz), 8.49 (d, 1, J = 8.8 Hz), mle 290 (M+, 521, 273 (80), 259 (211, 256 (36). HRMS, calcd 8.03 (dd, 1, J = 7.9 Hz, J = 1.2 Hz), 7.93 (d, 1, J = 8.8 Hz), for C19H1403: mfe 290.0943, found m le 290.0944. 8,9-Dihydro-2-methoxyy-4H-cyclopenta[&fl-(6-phenan- 7.92 (s, 11, 7.59-7.70 (m, 21, 7.34 (s, 11, 7.26 (s, 11, 4.39 (s, 21, 3.99 (s, 3). Anal. Calcd for C20H140: C, 88.86; H, 5.22. thrylcarbony1)propanoic acid (15a). To a mixture of Found: C, 88.97; H, 5.27. succinic anhydride (2.25 g, 22.5 mmol) and AC13 (7.48 g, 56 4H-Cyclopenta[&flchrysen-2-ol(1Sb). To a solution of mmol) in 100 mL of dry CHzClz at 0 "C under argon was added 18a (450 mg, 1.66 mmol) in 10 mL of CHzClz at 0 "C under 14b (5 g, 22.5 mmol) over 10 min. The mixture was stirred at argon was added 5 mL of BBr3, and the mixture was stirred ambient temperature for 24 h and then cooled in a n ice bath at this temperature for 1h and then poured into crushed ice. and hydrolyzed with cold dilute HC1. Following evaporation The product was extracted with 100 mL of CHzClz and then of the CHZC12 in vacuo, the crude keto acid was filtered, washed with water, dried and evaporated to provide 18b (380 washed with dilute HCl and water, dried, and washed with mg, 89%) as a white solid, mp 218-220 "C: 'H NMR 6 8.66 hexane. Recrystallization from acetone provided pure 15a (d, 1,J = 8.0 Hz), 8.52 (d, 1,J = 8.8 Hz), 8.05 (d, 1,J = 7.9 (6.72 g, 93%)as pale yellow needles, mp 209-210 "C: lH NMR Hz), 7.95 (5, l), 7.89 (d, 1,J = 8.8 Hz), 7.60-7.70 (m, 2), 7.29 (DMSO-&) 6 7.96 (9, 11, 7.78 (5, 11, 7.02 (s, 11, 6.80 (s, 11, 3.91 (s, l),7.25 (s, l),5.01 (s, 1, disappeared with DzO), (s, 2). MS, ( 8 , 21, 3.80 (s, 31, 3.25 (t, 2, J = 6.3 Hz), 3.09 (s, 41, 2.59 (t, 2, m le (relative abundance) 256 (M+,loo%), 239 (301, 226 (55); J = 6.3 Hz). Anal. Calcd for C20K1804.HzO: C, 72.50; H, 5.74. 128 (35). Anal. Calcd for C19H120: C, 89.04; H, 4.72. Found: C, 72.79; H, 5.66. 8,9-Dihydro-2-methoxy-4H-cyclopenta[deflphenan- Found: C, 88.97; H, 4.77. 4H-Cyclopenta[deflchrysene-l,2-dione (19). To a soluthrene-6-butyricAcid (15b). A solution of 15a (5.5 g, 18 tion of 18b (300 mg, 1.2 mmol) in 60 mL of CHzClz was added mmol), hydrazine hydrate (11.3 mL), and KOH (5 g) in 150

argon was added m-CPBA (500 mg, 2.9 mmol). The solution was stirred at 0 "C for 1 h. Stirring was continued at room temperature until TLC indicated disappearance of the starting material (2 h). The solution was concentrated to -20 mL under vacuum without heating, and the residue was diluted with ice cold EtOAc (100 mL), washed with ice cold 10%NaOH (aqueous) and ice cold HzO until neutral. The organic layer was dried over NazS04 (10 min). The entire workup should be done as rapidly as possible at low temperature in order t o minimize decomposition of the diol epoxide. The crude product was triturated with ether to give the diol epoxide 3 (43 mg, 81%) as tiny yellow crystals which decomposed at 210 "C: lH NMR 6 8.22 (d, 1,J = 9.0 Hz), 8.00 (s, 11, 7.92 (d, 1,J = 9.0 Hz), 7.92(d, 1,J=7.8Hz), 7.71 (d, 1,J=7.1 Hz), 7.62(d, l), 4.86 (d, 1, J = 4.5 Hz), 4.53 (d, 1, J = 8.7 Hz), 4.34 (bs, 21, 3.81 (m, 2). MS, mfe 290 (M+, 581, 272 (1001, 256 (441, 243 (66). HRMS, calcd for C19H1403: mfe 290.0943 found mfe 290.0966.

Dai et al.

4 drops of Adogen 464,50mL of 1/6M KHzPO4, and 1.2g of Fremy's salt. The mixture was stirred under argon for 1 h. Red crystals of the quinone precipitated from the reaction mixture. The solvent was evaporated under vacuum, and the red solid was filtered and triturated with ether and acetone to yield the quinone 19 (258 mg, 82%), mp 162-164 "C dec:

J. Org. Chem., Vol. 60, No. 15, 1995 4911 trans-1,2-Dihydroxy-anti-3,3a-epoxy-1,2,3,3a-tetrahydro-4H-cyclopenta[&flchrysene (2). To a solution of 20 (30mg, 0.11mmol) in 3 mL of dry THF at 0 "C under argon was added m-CPBA (86mg, 0.5mmol), and the mixture was stirred for 30 min. The solution was diluted with ether (30 mL) and washed with ice-cold 2 N NaOH and with ice water

lHNMR68.53(dd,l,J=8.8Hz,J=3.6Hz),8.41(d,l,J= and then dried over NaS04. The solvent was removed by 8.3Hz), 8.09(d, 11,7.92(dd, 1,J = 8.8 Hz,J = 4.0Hz), 7.66evaporation under vacuum avoiding heating, and the residue 7.70(m, 21,7.63(s, 1),6.47(s, 1),4.22(s, 2);UV (ethanol) 1max was triturated with cold ether to afford 2 (22 mg, 70%) as a 289 ( E 21 540), 255 (17920), 215 (11540) nm. MS,mle white solid, mp 143-146 "C dec: 'H NMR (DMSO-&) 6 8.66 (relative abundance) 270 (M+, loo%), 243 (201,107 (151,128 (dd, 1,J = 8.4Hz,J = 1.4Hz), 8.53(d, 1,J = 8.3 Hz), 7.95 (35);HRMS calcd for C19HloOZ 270.0682,found 270.0682. (dd, 1,J = 8.6Hz, J = 1.9Hz),7.71(d, l), 7.68(s, 11,7.59trans-1,2-Dihydroxy-1,2-dihydro-4H-cyclopenta~defl-7.65(m, 2), 5.76(d, 1,J = 6.3Hz,disappeared with DzO), 5.63 chrysene (20). To a solution of 19 (200 mg, 0.74mmol) in (d, 1,J = 5.3Hz,disappeared with DzO), 4.65 (t, 1,J = 8.1 50 mL of ethanol was added 600 mg of NaBH4, and 0 2 was Hz,changed to d, J = 8.1Hz with DzO), 4.05(s, 11,3.80(two bubbled through the solution for 48 h. The mixture was overlapping d, J = 8.1Hz,J= 18.9Hz), 3.50(d, 1,J = 18.9 partitioned between EtOAc and water and worked up in the Hz); UV (ethanol) Amax 369 ( E 3500),302 (61201,257 (389401, usual manner12 t o afford the crude dihydrodiol. Chromatog215 (19440)nm. MS, m l e (relative abundance) 290 (M+,52), raphy on silica gel gave pure 20 (162mg, 80%) as a white solid, 272 (45),270 (70),244(71);HRMS calcd for C19H1403 290.0943, 195-197 "C: 'H NMR 6 8.68(d, 1,J = 7.2Hz), 8.41 (d, 1,J found 290.0943. = 8.2Hz),7.97(dd, 1,J = 7.5Hz,J = 1.6Hz), 7.69(d, 11,7.64 (s, I),7.57-7.62(m, 2),5.90(d, 1,J = 1.6Hz),5.50(d, 1,J = Acknowledgment. This research was supported by 7.5Hz,disappeared with DzO), 5.19(d, 1,J = 7.2Hz,OH, grants from the National Institute for Environmental disappeared with DzO), 4.86(t, 1,J = 5.9Hz,changed t o d, J = 6.0Hz with DzO), 4.52(br s, l), 3.99(s, 2); UV (ethanol) Health Sciences (ES 04266) and the American Cancer A,,, 276 ( E 35 700),245 (2750), 220 (44360),197 (35160)nm. Society (CN-22). Anal. Calcd for C19H1402: C, 83.21;H,5.10. Found: C, 83.01; 509503567 H,5.21.